Breast Cancer Clinical Trial
Official title:
Meriva for Treatment-induced Inflammation and Fatigue in Women With Breast Cancer
The main purpose of the investigation is to determine if curcumin reduces NF-kB DNA binding and ultimately its downstream mediator IL-6 in patients receiving XRT for their breast cancer after having completed chemotherapy. Patients who have received prior chemotherapy will be eligible, because we have found that this enriched population is at particular risk for exhibiting increased NF-kB DNA binding and IL-6 following XRT.
As many as 60% of breast cancer (BrCA) patients receiving radiation are known to develop
fatigue with about 30% suffering persistent fatigue several months to years after treatment
completion (12-23). The physical, psychological, and molecular mechanisms by which patients
develop fatigue are poorly understood and most likely multi-factorial. One pathway that has
received considerable attention is nuclear factor-kappa B (NF-kB)(24). The NF-kB pathway has
emerged as having an important role not only in cancer treatment resistance but in the
development of fatigue. NF-kB activation leads to over expression of interleukin (IL)-1beta,
IL-6, and tumor necrosis factor (TNF)-alpha, all factors related to inflammation and factors
that have been found to be upregulated in patients receiving radiation as well as BrCA
survivors with fatigue (25-29). A recently published study looking at TNF-alpha, fatigue and
cachexia in cancer patients receiving docetaxol showed that NF-kB is upregulated in fatigued
patients and that agents which inhibit TNF-alpha lead to better tolerance of chemotherapy
dose escalation (30). Work by our group and others has shown that ionizing radiation
increases NF-kB pathway activity in circulating immune cells (as well as within breast cancer
cells) and that this effect is most pronounced in women previously treated with chemotherapy
(31, 32). Our work has shown that the NF-kB pathway activity in circulating immune cells is
also related to fatigue development in BrCA patients treated with radiation and that patients
most at risk for persistent fatigue and NF-kB pathway activity are those who have received
chemotherapy for their breast cancer (31).
Curcumin, a known inhibitor of NF-kB, has been shown to decrease NF-kB activation in human
participants. In a recent study, 8 grams of curcumin by mouth daily for 8 weeks was well
tolerated in patients with pancreatic cancer and other pre-malignant conditions with no
associated toxicities (6, 8). Although there is concern over the body's absorption of
curcumin, the bioavailability of curcumin in the study of pancreatic cancer patients was
shown, with peak drug levels at 22 to 41ng/mL that remained relatively constant over the
first 4 weeks of treatment with 8 grams of curcumin daily (8). Clinical trials with daily
dosages of 1,125 to 2,500mg have also confirmed the safety of curcumin and also shown its
ability to decrease inflammation in patients with rheumatoid arthritis and in post-operative
patients (6, 33, 34). In vivo murine models of chronic fatigue syndrome have also shown that
curcumin may also alleviate symptoms of fatigue (35). While these studies are promising, very
little is known about the capacity of Meriva to inhibit NF-kB in women treated for BrCA. We
hypothesize that oral Meriva, a known inhibitor of NF-kB, may be used to decrease levels of
NF-kB activity in BrCA patients previously treated with chemotherapy who go on to receive
radiotherapy (XRT), a carefully chosen group of patients at particular risk for high levels
of NF-kB DNA binding (a direct measure of NF-kB pathway activity).
We have chosen to administer oral Meriva, 500mg BID, in our patient population based on the
above data. Meriva-500 is a curcumin formulation that also contains phosphatidylcholine,
derived from soy that has been shown to aid in absorption of curcumin (9), permitting a lower
overall dose of curcumin. Of note, 1000 mg Meriva contains 200 mg curcuminoids (>90%
curcumin).
By decreasing activity of NF-kB and ultimately plasma IL-6, fatigue may improve in BrCA
patients taking Meriva. Results from this study will contribute to the limited research
available on the capacity of curcumin treatment, including Meriva, to inhibit NF-kB
activation in vivo as well as symptoms of fatigue associated with excessive NF-kB pathway
activity in BRCA patients.
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